Mouse models and strain-dependency of Chédiak-Higashi syndrome-associated neurologic dysfunction

Abstract

Chédiak-Higashi syndrome (CHS) is a lethal disorder caused by mutations in the LYST gene that involves progressive neurologic dysfunction. Lyst -mutant mice exhibit neurologic phenotypes that are sensitive to genetic background. On the DBA/2J-, but not on the C57BL/6J-background, Lyst -mutant mice exhibit overt tremor phenotypes associated with loss of cerebellar Purkinje cells. Here, we tested whether assays for ataxia could measure this observed strain-dependency, and if so, establish parameters for empowering phenotype- and candidate-driven approaches to identify genetic modifier(s). A composite phenotypic scoring system distinguished phenotypes in Lyst -mutants and uncovered a previously unrecognized background difference between wild-type C57BL/6J and DBA/2J mice. Accelerating rotarod performance also distinguished phenotypes in Lyst -mutants, but at more advanced ages. These results establish that genetic background, Lyst genotype, and age significantly influence the severity of CHS-associated neurologic deficits. Purkinje cell quantifications likewise distinguished phenotypes of Lyst -mutant mice, as well as background differences between wild-type C57BL/6J and DBA/2J mice. To aid identification of potential genetic modifier genes causing these effects, we searched public datasets for cerebellar-expressed genes that are differentially expressed and/or contain potentially detrimental genetic variants. From these approaches, Nos1 , Prdx 2, Cbln3 , Gnb1 , Pttg1 were confirmed to be differentially expressed and leading candidates.

Lysosomal size matters

“…[184][185][186] Unfortunately, the neurologic phenotypes displayed by LYST-mutant mice were found to depend on genetic background. 187 Nevertheless, the characterization of Lyst-mutant beige mice indicated that LYST controls phagosomal maturation, triggered as a response to bacterial infection. It specifically regulates the formation of endolysosomal/phagosomal compartments required for the activation of TIR domain-containing adapterinducing interferon β (TRIF) dependent Toll like receptor signaling.…”

Glyoxalase 1 Inhibitor Alleviates Autism-like Phenotype in a Prenatal Valproic Acid-Induced Mouse Model

“…Recent studies showed that overexpression of GLO1 alleviates MG accumulation, whereas suppression of GLO1 increases MG levels . Given the vital roles of GLO1 and MG in glucose, protein, and fatty acid metabolism, multiple lines of evidence have implicated dysregulation of GLO1 and MG in diabetic complications, aging, carcinogenesis, and behavioral phenotypes, , including anxiety, schizophrenia, depression, and autism.…”

Phenotype assessment for neurodegenerative murine models with ataxia and application to Niemann–Pick disease, type C1

“…Guyenet et al developed a valuable composite phenotypic scoring system (CPSS) in 2010 to describe mouse models of cerebellar ataxia measuring: ledge test, hindlimb clasping, gait, and kyphosis ( Guyenet et al, 2010 ). This scoring system was used to distinguish strain-dependent phenotypes in Lyst -mutant mice ( Hedberg-Buenz et al, 2019 ), while a modified version was used in the context of NPC ( Alam et al, 2016 ). A comparison between the different scoring systems is provided in Table 1 .…”